The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
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T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s<br />
approaches is illustrated by a decrease in rabbit eye tests in the UK from approximately<br />
4,000 in 1995 to 1,100 in 2003. 6<br />
9.13 Acute systemic toxicity is assessed by the administrati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> a single dose <str<strong>on</strong>g>of</str<strong>on</strong>g> compound, typically<br />
to rats and mice, orally, dermally or by inhalati<strong>on</strong>. For pharmaceuticals, the main aims <str<strong>on</strong>g>of</str<strong>on</strong>g> these<br />
studies are to determine the nature (including delayed toxicity) and durati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> any acute toxic<br />
resp<strong>on</strong>se. <str<strong>on</strong>g>The</str<strong>on</strong>g>y also determine the maximum n<strong>on</strong>-lethal dose and provide preliminary<br />
informati<strong>on</strong> relevant to single exposure or over-dosage in humans (see paragraph 9.39). 7<br />
9.14 For industrial chemicals and agrochemicals, testing covers acute toxicity by oral, dermal and<br />
inhalati<strong>on</strong> routes <str<strong>on</strong>g>of</str<strong>on</strong>g> exposure. <str<strong>on</strong>g>The</str<strong>on</strong>g> informati<strong>on</strong> obtained is used primarily to ascribe a chemical<br />
to bands <str<strong>on</strong>g>of</str<strong>on</strong>g> acute toxic effect, which restricts how the materials may be used, and thus the<br />
extent <str<strong>on</strong>g>of</str<strong>on</strong>g> human exposure by the routes <str<strong>on</strong>g>of</str<strong>on</strong>g> exposure which have been evaluated. In the past,<br />
in the UK and elsewhere, acute systemic toxicity was investigated by the use <str<strong>on</strong>g>of</str<strong>on</strong>g> lethal-dose<br />
tests, in which the oral dose causing the death <str<strong>on</strong>g>of</str<strong>on</strong>g> 50 percent <str<strong>on</strong>g>of</str<strong>on</strong>g> the treated <str<strong>on</strong>g>animals</str<strong>on</strong>g> (the LD 50<br />
value) was determined. 8 Such tests used at least 30 <str<strong>on</strong>g>animals</str<strong>on</strong>g> per test chemical and required<br />
death <str<strong>on</strong>g>of</str<strong>on</strong>g> the <str<strong>on</strong>g>animals</str<strong>on</strong>g> as an endpoint, regardless <str<strong>on</strong>g>of</str<strong>on</strong>g> the suffering caused. In 2001 the OECD<br />
agreed that the LD 50 test for acute oral toxicity should be abolished and deleted from the<br />
OECD manual <str<strong>on</strong>g>of</str<strong>on</strong>g> internati<strong>on</strong>ally accepted test guidelines by the end <str<strong>on</strong>g>of</str<strong>on</strong>g> 2002 (see paragraphs<br />
9.4 and 12.8). 9 Several alternative methods have been developed which use fewer <str<strong>on</strong>g>animals</str<strong>on</strong>g> and<br />
in some cases replace death as the endpoint with signs <str<strong>on</strong>g>of</str<strong>on</strong>g> significant toxicity instead.<br />
Informati<strong>on</strong> <strong>on</strong> similar chemicals is used to guide the selecti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> initial dose levels and the<br />
tests are designed to avoid or minimise lethality or severe toxicity. <str<strong>on</strong>g>The</str<strong>on</strong>g>se methods have<br />
replaced the LD 50 test for acute oral toxicity, but several acute tests such as those <str<strong>on</strong>g>involving</str<strong>on</strong>g><br />
inhalati<strong>on</strong>, dermal and eye exposure have yet to be modified. <str<strong>on</strong>g>The</str<strong>on</strong>g>y are still used<br />
internati<strong>on</strong>ally for tests <strong>on</strong> birds and, for some purposes, also <strong>on</strong> mammals. 10 Lethal-dose tests<br />
are also still used to assess the safety <str<strong>on</strong>g>of</str<strong>on</strong>g> biological products, such as vaccines (Box 8.5), and<br />
certain foods, such as shellfish, for the presence <str<strong>on</strong>g>of</str<strong>on</strong>g> toxins (see paragraph 9.37).<br />
CHAPTER 9 ANIMAL USE IN TOXICITY STUDIES<br />
9.15 <str<strong>on</strong>g>The</str<strong>on</strong>g> approach to assessing the acute toxicity <str<strong>on</strong>g>of</str<strong>on</strong>g> pharmaceuticals differs from that described<br />
above, in that maximum tolerated dose (MTD) studies are carried out to aid the later process<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> dose selecti<strong>on</strong>. <str<strong>on</strong>g>The</str<strong>on</strong>g>se tests <str<strong>on</strong>g>of</str<strong>on</strong>g>ten replace acute studies, especially in the case <str<strong>on</strong>g>of</str<strong>on</strong>g> larger<br />
species such as the dog and primates which are used to complement and verify earlier<br />
findings in rodents. <str<strong>on</strong>g>The</str<strong>on</strong>g>y involve steadily increasing the dose given to an animal (single or a<br />
number <str<strong>on</strong>g>of</str<strong>on</strong>g> c<strong>on</strong>secutive doses), until adverse effects indicate that an MTD has been reached.<br />
This is normally determined by careful observati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the <str<strong>on</strong>g>animals</str<strong>on</strong>g>, but there is no universally<br />
accepted definiti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the MTD and effects such as vomiting and c<strong>on</strong>vulsi<strong>on</strong>s may occur and<br />
are sometimes used as signs <str<strong>on</strong>g>of</str<strong>on</strong>g> the MTD (see paragraphs 9.34–9.45).<br />
6 See Home Office (2004) Statistics <str<strong>on</strong>g>of</str<strong>on</strong>g> Scientific Procedures <strong>on</strong> Living Animals Great Britain 2003 (Norwich: HMSO).<br />
7 <str<strong>on</strong>g>The</str<strong>on</strong>g> studies provide informati<strong>on</strong> that may support selecti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> dose levels for repeated-dose toxicity studies, in vivo<br />
genotoxicity tests (see paragraphs 9.20-9.21) and, subsequently, first human exposure studies.<br />
8 <str<strong>on</strong>g>The</str<strong>on</strong>g> OECD gives the definiti<strong>on</strong> as the dose that can be expected to cause death in 50 percent <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g> when administered<br />
by the oral route.<br />
9 OECD (2001) OECD Test Guideline 401 will be deleted: A Major Step in Animal Welfare: OECD Reaches Agreement <strong>on</strong> the<br />
Abolishment <str<strong>on</strong>g>of</str<strong>on</strong>g> the LD 50 Acute Toxicity Test, available at:<br />
http://www.oecd.org/document/52/0,2340,en_2649_34377_2752116_1_1_1_1,00.html. Accessed <strong>on</strong>: 27 Apr 2005; <str<strong>on</strong>g>The</str<strong>on</strong>g> UK ceased<br />
the practice <str<strong>on</strong>g>of</str<strong>on</strong>g> the LD 50 test in 1999 (APC (1999) Press release: LD 50 Test - Changes To Licensing Procedures, available at:<br />
http://www.apc.gov.uk/press_releases/991021.htm. Accessed <strong>on</strong>: 27 Apr 2005). In the US, Envir<strong>on</strong>mental Protecti<strong>on</strong> Agency<br />
guidelines describe the LD 50 test as standard for pesticides and toxic substances although state that it may be unnecessary in<br />
certain circumstances (Envir<strong>on</strong>ment Protecti<strong>on</strong> Agency (1998) Health Effects Test Guidelines OPPTS 870.1100<br />
Acute Oral Toxicity, available at: http://www.epa.gov/docs/OPPTS_Harm<strong>on</strong>ized/870_Health_Effects_Test_Guidelines/Series/870-<br />
1100.pdf. Accessed <strong>on</strong>: 27 Apr 2005.<br />
10 OECD (2002) OECD guidelines for the testing <str<strong>on</strong>g>of</str<strong>on</strong>g> chemicals: Proposal for a new guideline 223 – Avian acute oral toxicity test,<br />
available at: http://www.oecd.org/dataoecd/16/41/1836204.pdf. Accessed <strong>on</strong>: 27 Apr 2005.<br />
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